ArticleAmerican journal of translational research2020
Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells.
Article in American journal of translational research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Reawakening Differentiation Therapy in Acute Myeloid Leukemia: A Comprehensive Review of ATRA-Based Combination Strategies.Current oncology (Toronto, Ont.) · 2026Review
- FTO effects the proliferation, invasion, and glycolytic metabolism of colon cancer by regulating PKM2.Journal of cancer research and clinical oncology · 2025Article
- Combination of Ethacrynic Acid and ATRA Triggers Differentiation and/or Apoptosis of Acute Myeloid Leukemia Cells through ROS.Anti-cancer agents in medicinal chemistry · 2024Article
- Unlocking therapeutic potential: integration of drug repurposing and immunotherapy for various disease targeting.American journal of translational research · 2023Review
- Combination of midostaurin and ATRA exerts dose-dependent dual effects on acute myeloid leukemia cells with wild type FLT3.BMC cancer · 2022Article
Corrections and comments
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Authors and funding
8 authors.
Funding
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Abstract
All-trans retinoic acid (ATRA) is considered to be the sole clinically-useful differentiating agent in the treatment of acute myeloid leukemia (AML). However, ATRA has been effective only in acute promyelocytic leukemia (APL) but not other subtypes of AML. Therefore, discovering strategies to sensitize cells to ATRA may lead to the development of ATRA-based treatments in non-APL AML patients. In the present study, a clinically-achievable concentration of enzastaurin enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as non-APL AML primary cells. Furthermore, it also restored ATRA sensitivity in ATRA-resistant cell line, HL-60Res. Mechanistically, in all these cell lines, enzastaurin-ATRA (enz-ATRA) co-treatment enhanced the protein levels of PU.1, CCAAT/enhancer-binding protein β (C/EBPβ) and C/EBPε. The activity of protein kinase C β (PKCβ) was suppressed by enz-ATRA treatment in HL-60 and HL-60Res cells. However, another PKCβ-selective inhibitor mimicked the cellular and molecular effects of enzastaurin only in HL-60 cells. Furthermore, in U937 cells, enz-ATRA activated MEK and ERK, and a MEK-specific inhibitor suppressed enz-ATRA-triggered differentiation and reduced the protein levels of PU.1, C/EBPβ and C/EBPε. Enz-ATRA activated Akt in HL-60 and HL-60Res cells. However, an Akt inhibitor blocked enz-ATRA-triggered differentiation and restored the protein levels of PU.1, C/EBPβ and C/EBPε only in HL-60Res cells. Therefore, PKCβ inhibition, MEK/ERK and Akt activation were involved in enz-ATRA-induced differentiation in HL-60, U937 and HL-60Res cells, respectively, via modulation of the protein levels of C/EBPβ, C/EBPε and PU.1. Taken together, our findings may help to guide novel therapeutic strategies for AML patients.
Indexed as
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